Review series The Journal of Clinical Investigation http://www.jci.org Volume 118 Number 4 April 2008 1291 Pneumonia research to reduce childhood mortality in the developing world J. Anthony G. Scott, 1,2 W. Abdullah Brooks, 3 J.S. Malik Peiris, 4 Douglas Holtzman, 5 and E. Kim Mulholland 6 1 Wellcome Trust/KEMRI Research Programme, Kilifi, Kenya. 2 Nuffield Department of Clinical Medicine, University of Oxford, Oxford, United Kingdom. 3 Centre for Health and Population Research, International Centre for Diarrhoea Disease Research, Dhaka, Bangladesh. 4 Department of Microbiology, University Pathology Building, Queen Mary Hospital, University of Hong Kong, Hong Kong Special Administrative Region, People’s Republic of China. 5 Infectious Diseases Development, Global Health Program, Bill and Melinda Gates Foundation, Seattle, Washington, USA. 6 Infectious Disease Epidemiology Unit, London School of Hygiene and Tropical Medicine, London, United Kingdom. Pneumonia is an illness, usually caused by infection, in which the lungs become inflamed and congested, reduc- ing oxygen exchange and leading to cough and breathlessness. It affects individuals of all ages but occurs most frequently in children and the elderly. Among children, pneumonia is the most common cause of death worldwide. Historically, in developed countries, deaths from pneumonia have been reduced by improvements in living condi- tions, air quality, and nutrition. In the developing world today, many deaths from pneumonia are also preventable by immunization or access to simple, effective treatments. However, as we highlight here, there are critical gaps in our understanding of the epidemiology, etiology, and pathophysiology of pneumonia that, if filled, could accelerate the control of pneumonia and reduce early childhood mortality. Introduction Every year 1.9 million children under 5 years of age die from pneumonia (1). Indeed, it is the leading cause of child death in the world. Pneumonia is an acute illness in which the alveolar air spaces of the lung become inflamed and filled with fluid and white blood cells, giving rise to the appearance of consolidation on the chest radiograph. It can be caused by bacterial, viral, or parasitic infection as well as by noninfectious agents. Most severe cases of pneumonia are caused by bacteria, of which the most important are Streptococcus pneumoniae (pneumococcus) and Hae- mophilus influenzae. In developing countries, where patients are often treated without seeing a doctor, the WHO defines clini- cal pneumonia simply as an acute episode of cough or difficulty breathing associated with an increased respiratory rate (2). Pneumonia is a disease of all ages, and in adult medical wards across the developing world it is one of the most common admis- sion diagnoses. In contrast to the industrialized world, pneu- monia is found characteristically in younger adults, who have a substantial inpatient mortality of 5%–23% (3). The pathogens causing pneumonia in children and adults are similar, and most respiratory pathogens are transmitted effectively between gen- erations within households. In the United States, preventing pneumonia in children by vaccinating against pneumococcal disease has resulted in less pneumonia in adults (4). However, little is known about adult pneumonia in developing countries, and research is rare outside the context of emerging infections (3). There are thus considerable opportunities for pneumonia research on adults. However, in this Review, we concentrate on childhood pneumonia and specifically on research to reduce the unacceptable magnitude of child deaths from this disease. Historically, pneumonia was the main cause of child death in developed countries, and in the United States in 1900, it is esti- mated that pneumonia killed 47 of every 1,000 children before the age of 5 years (5). Improvements in nutrition and living standards in the United States in the first 40 years of the 20th century led to a substantial reduction in pneumonia mortality well before antibiotics became available as an effective treatment (Figure 1 and refs. 6–8). However, in the low-income countries of Asia and Africa, pneumonia is still the main cause of child death. In developing countries, over one-quarter of children have an episode of clinical pneumonia each year throughout the first 5 years of their lives (9). On average, 2%–3% of children each year have pneumonia severe enough to require hospitalization, and many of these disease episodes are potentially fatal (9). Thus, for every 1,000 children born, about 100–150 episodes of severe pneumonia arise during the first 5 years of life, most during the first 2 years. Approximately 21% of child deaths are due to pneu- monia (1), and many developing countries have mortality rates of 60–100 per 1,000 children under 5 years of age (10); this suggests that of every 1,000 children born alive, 12–20 die from pneumo- nia before their fifth birthdays. Although we know the number of children who die of pneumo- nia in developing countries, few of the causal factors leading to death have been elucidated. Mortality is associated with poverty and with malnutrition; critically, we do not yet know the extent to which it is caused by lack of access to health care. If access to care is inversely related to mortality, the impact of new diagnos- tics, medical treatments, and vaccines will be substantially con- strained. Therefore, the first priority for pneumonia research is a better understanding of the epidemiology of fatal pneumonia. Increased understanding of this, as well as more detailed infor- mation about the etiology and pathophysiology of the disease, should guide new approaches to tackle the immense global prob- lem of child deaths from pneumonia. Nonstandard abbreviations used: Hib, Haemophilus influenzae type b; IMCI, Inte- grated Management of Childhood Illness; PCV, pneumococcal conjugate vaccine; RSV, respiratory syncytial virus. Conflict of interest: E.K. Mulholland is a member of the Global Alliance for Vaccines and Immunization’s Hib Initiative. W.A. Brooks has conducted research funded by the Bill and Melinda Gates Foundation, but was not the direct recipient of the grant. J.A.G. Scott and E.K. Mulholland are members of the PneumoCarr consortium, which received funding from the Bill and Melinda Gates Foundation through its initiative “Grand Challenges in Global Health.” The remaining authors have declared that no conflict of interest exists. Citation for this article: J. Clin. Invest. 118:1291–1300 (2008). doi:10.1172/JCI33947.